VA Class:AM119

AHFS Class:

• Carbapenems 8:12.07.08

Generic Name(s):

• Imipenem and Cilastatin

• Imipenem

• Cilastatin Sodium

Chemical Name:

• [5 R -[5α,6α(R*)]]-6-(1-Hydroxyethyl)-3-[[2-(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylic acid monohydrate mixt. with [ R -[ R *, S *-(Z)]]-7-[(2-Amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl) carbonyl]amino]-2-heptenoic acid monosodium salt

• [5 R -[5α,6α(R*)]]-6-(1-Hydroxyethyl)-3-[[2-(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2carboxylic acid monohydrate

• [ R -[ R *, S *-( Z )]]-7- [(2-Amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl) -carbonyl]amino]-2-heptenoic acidmonosodium salt

Molecular Formula:

• C₁₂H₁₇N₃O₄S•H₂

Imipenem and cilastatin sodium is a fixed combination of imipenem monohydrate (a semisynthetic carbapenem β-lactam antibiotic)1,2,4,6,148,196,198 and cilastatin sodium (a renal dehydropeptidase inhibitor that prevents renal metabolism of imipenem). 1,2,6,101,125,137,140,141,145,148,196,198

Imipenem and cilastatin sodium is used for the treatment of lower respiratory tract, intra-abdominal, gynecologic, skin and skin structure, or bone and joint infections caused by susceptible gram-negative and gram-positive bacteria.1,6,146,159,163,164,167,170,172,178,179,180,181,182,183,184,198,200,215,240 The drug also is used for the treatment of complicated or uncomplicated urinary tract infections, septicemia, or endocarditis caused by susceptible bacteria.1,6,146,159,163,164,170,172,180,181,198,215,240

Because of its wide spectrum of activity, one of the principal uses of IV imipenem and cilastatin is the treatment of polymicrobial bacterial infections.1,6,145,146,159,163,164,172,178,179,181,182,184,196,198,200,201,215,240,543 The drug is useful for empiric IV therapy1,146,240 of serious nosocomial infections that may include both gram-positive and gram-negative aerobic bacteria as well as anaerobic bacteria.1,159,163,164,198,201,240 IV imipenem and cilastatin generally should not be used for the treatment of monobacterial infections when an anti-infective agent with a narrower spectrum of activity would be effective when used alone1,210,240 or for the treatment of most community-acquired infections caused by organisms susceptible to other anti-infective agents.210,215,240 IV imipenem and cilastatin has been effective in the treatment of monobacterial and polymicrobial bacterial infections that failed to respond to other anti-infective agents, including cephalosporins, penicillins, and/or aminoglycosides.1,145,200,210 The manufacturer states that the drug should not be used in the treatment of meningitis because safety and efficacy of the drug in these infections have not been definitely established.1

Gram-positive Aerobic Bacterial Infections

Infections Caused by Aerobic Gram-positive Cocci

Imipenem and cilastatin has been used for the treatment of serious lower respiratory tract infections caused by susceptible penicillinase-producing Staphylococcus aureus ;1,164,167,172 serious complicated or uncomplicated urinary tract infections1,146,158,167,172 or septicemia1,146,164,167,181 caused by susceptible penicillinase-producing S. aureus or Enterococcus faecalis ; serious skin and skin structure,1,146,164,167,170,172,179,184 bone and joint,1,146,164,167,182 or intra-abdominal infections1,179 caused by susceptible penicillinase-producing S. aureus , S. epidermidis , or E. faecalis ; serious gynecologic infections1,146,178 caused by susceptible S. epidermidis , group B streptococci, enterococci, or penicillinase-producing S. aureus ; or endocarditis caused by penicillinase-producing S. aureus .1,146,186 However, imipenem and cilastatin generally is not considered an initial drug of choice for these infections.210

Imipenem and cilastatin has also been used in the treatment of polymicrobial infections in which Streptococcus pneumoniae , S. pyogenes (group A β-hemolytic streptococci), or nonpenicillinase-producing S. aureus is one of the causative organisms,1 but other anti-infective agents with a narrower spectrum of activity (e.g., natural penicillins) usually are indicated for the treatment of monobacterial infections caused by these gram-positive aerobic cocci.1,210,261

Imipenem and cilastatin usually is effective when used in the treatment of infections caused by penicillinase-producing S. aureus and has been effective when used alone in patients for the treatment of endocarditis caused by penicillinase-producing S. aureus .146,186,198 However, penicillinase-resistant penicillins are generally the drugs of choice for the treatment of infections caused by susceptible penicillinase-producing staphylococci.261 Imipenem and cilastatin has been used IV in the treatment of infections caused by methicillin-resistant staphylococci;206 however, efficacy of the drug in these infections and adequate in vitro methods for determining susceptibility of MRSA to imipenem have not been established.7,18,137,206

Nocardia Infections

Imipenem and cilastatin has been effective when used for the treatment of infections caused by Nocardia , including pulmonary nocardiosis caused by N. asteroides and primary cutaneous nocardiosis.293,294,295 Co-trimoxazole or a sulfonamide alone usually is recommended for the treatment of mild Nocardia infections;261,292 alternatives include a fluoroquinolone or a carbapenem.292 Multiple-drug regimens are recommended for the treatment of more severe Nocardia infections (e.g., pulmonary infections, disseminated disease, CNS involvement) or infections in immunocompromised patients.292 Multiple-drug regimens usually should include co-trimoxazole, amikacin, and a carbapenem (imipenem or meropenem).261,292

Rhodococcus Infections

Imipenem and cilastatin has been used in conjunction with other anti-infectives (e.g., vancomycin) for the treatment of infections caused by Rhodococcus equi .261,308 R. equi has been identified as a cause of pulmonary infections (e.g., lung abscess) in immunocompromised individuals such as patients with human immunodeficiency virus (HIV) infection and solid organ transplant recipients.298,299,307,308 While optimum regimens for the treatment of these infections have not been identified and a 10- to 14-day regimen of an effective anti-infective may be sufficient for the treatment of pulmonary infections in some patients,308 a multiple-drug regimen usually has been recommended and prolonged treatment may be required.297,298,299,307,308

Gram-negative Aerobic Bacterial Infections

Infections Caused by Enterobacteriaceae

Imipenem and cilastatin is used in the treatment of serious lower respiratory tract infections or septicemia caused by susceptible Enterobacter , Escherichia coli , Klebsiella , or Serratia marcescens ;1,164,170,172,181,183 serious complicated or uncomplicated urinary tract infections caused by susceptible Enterobacter , E. coli , Klebsiella , Morganella morganii , Proteus vulgaris , or Providencia rettgeri ;1,158,164,170,172,180 or serious bone and joint infections caused by susceptible Enterobacter .164,182 The drug is also used in the treatment of serious intra-abdominal infections caused by susceptible Citrobacter , Enterobacter , E. coli , Klebsiella , M. morganii , or Proteus ;1,164,172,179 serious gynecologic infections caused by susceptible Enterobacter , E. coli , Klebsiella , or Proteus ;1,178 or serious skin and skin structure infections caused by susceptible Citrobacter , Enterobacter , E. coli , Klebsiella , M. morganii , P. vulgaris , P. rettgeri , or Serratia .1,170,172,179,184

Imipenem and cilastatin has generally been effective when used alone in the treatment of serious infections caused by susceptible Enterobacteriaceae.158,164,170,172,179,180,181,182,183,184 Although some clinicians recommend that an aminoglycoside be used concomitantly if the drug is used for empiric therapy of nosocomial gram-negative bacteremia in seriously ill patients,210 other clinicians state that imipenem and cilastatin can generally be used alone for these infections unless there is a possibility that Pseudomonas aeruginosa may be present.210

Pseudomonas aeruginosa Infections

Imipenem and cilastatin is used in the treatment of intra-abdominal infections,1,164 skin and skin structure infections,1,164,184 complicated or uncomplicated urinary tract infections,158,164,173,180 septicemia,1,164,181 or bone and joint1,164,182 infections caused by susceptible Ps. aeruginosa .1,164,184 Because resistant strains of Ps. aeruginosa have emerged during imipenem and cilastatin therapy,6,137,146,153,157,162,163,164,171,173,174,183,191,198,222,240 in vitro susceptibility tests should be performed periodically when the drug is used in the treatment of infections caused by this organism.6,210 Some clinicians recommend concomitant use of an aminoglycoside when imipenem and cilastatin is used in the treatment of serious infections known or suspected to be caused by Ps. aeruginosa .137,146,153,157,162,163,164,173,174,183,191,196,198,210,240

Clinical improvement has been observed in some patients when imipenem and cilastatin was used for the treatment of acute exacerbations of bronchopulmonary Ps. aeruginosa infections in patients with cystic fibrosis;1,157,191,215 however, as with other anti-infective agents, a bacteriologic cure is rarely obtained and should not be expected in these patients.1,189,191,215

Acinetobacter Infections

Imipenem and cilastatin is used in the treatment of serious infections caused by Acinetobacter , including lower respiratory tract infections and skin and skin structure infections caused by these organisms.1,6,157 Some clinicians suggest that carbapenems (imipenem or meropenem) are drugs of choice for the treatment of Acinetobacter infections and recommend concomitant use of an aminoglycoside (amikacin, gentamicin, tobramycin) in severe infections.261

Burkholderia Infections

Imipenem and cilastatin has been used for the treatment of localized or septicemic melioidosis†,280,281,282,283,284 a potentially life-threatening disease caused by Burkholderia pseudomallei 280,282,283 (an aerobic, nonfermentative gram-negative bacilli resistant to many anti-infective agents).282 Ceftazidime or meropenem usually is the drug of choice for the treatment of melioidosis.261,280,281,282,283,284,285,292 Other drugs that have been recommended as alternative agents for the treatment of melioidosis include imipenem and cilastatin, co-trimoxazole, fixed combination of amoxicillin and clavulanate potassium (amoxicillin/clavulanate), or a 3-drug regimen of chloramphenicol, doxycycline, and co-trimoxazole.261,284,285,292 B. pseudomallei is difficult to eradicate, and relapse of melioidosis commonly occurs.280,281,283,285 Therefore, anti-infective therapy usually is continued for 6 weeks to 6 months; a parenteral anti-infective is given for at least 1-2 weeks followed by an oral anti-infective given for at least 3-6 months.280,281,283,292

Imipenem and cilastatin has been recommended for the treatment of glanders† caused by B. mallei .261,543 Although optimum regimens for the treatment of glanders have not been identified, imipenem and cilastatin is one of several options for the treatment of nodular skin and mucous membrane lesions caused by B. mallei based on results of in vitro susceptibility testing.543

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Imipenem and cilastatin is used in the treatment of infections caused by gram-positive and gram-negative anaerobic bacteria.1,169,172,176,177,178,179,181,184,201,543 The drug has been effective in the treatment of serious intra-abdominal infections caused by susceptible Bifidobacterium , Clostridium , Peptococcus , Peptostreptococcus , Eubacterium , or Propionibacterium ;1,179 serious gynecologic infections caused by susceptible Bifidobacterium , Peptococcus , Peptostreptococcus , or Propionibacterium ;1,176,178 or serious skin and skin structure infections caused by susceptible Peptococcus or Peptostreptococcus .1,179,184 Imipenem and cilastatin has also been effective in the treatment of septicemia or serious intra-abdominal, gynecologic, or skin and skin structure infections caused by susceptible Bacteroides , including B. fragilis , and in the treatment of serious intra-abdominal tract or skin and skin structure infections caused by susceptible Fusobacterium .1,176,178,179,181,184

Imipenem and cilastatin is used in the treatment of serious intra-abdominal infections of mild-to-moderate severity caused by susceptible Bacteroides (including B. fragilis , B. distasonis , B. thetaiotaomicron ), Fusobacterium , or Peptostreptococcus ;1 serious skin and skin structure infections of mild-to-moderate severity caused by susceptible Bacteroides , including B. fragilis ;1 or serious gynecologic infections of mild-to-moderate severity caused by susceptible P. intermedia or Peptostreptococcus .1

Imipenem and cilastatin has been effective when used alone in the treatment of mixed aerobic-anaerobic infections such as peritonitis, intra-abdominal abscess, and gynecologic infections.169,172,177,201 In several controlled studies, imipenem and cilastatin alone was at least as effective as gentamicin used in conjunction with clindamycin for the treatment of mixed aerobic-anaerobic bacterial infections.169,179,215

Endocarditis

Imipenem and cilastatin has been used for the treatment of endocarditis caused by susceptible penicillinase-producing S. aureus .1,146,186 However, guidelines from the American Heart Association (AHA) do not include imipenem and cilastatin as a recommended or alternative drug for the treatment of staphylococcal endocarditis in adults or pediatric patients.450,452

Respiratory Tract Infections

Imipenem and cilastatin has been used in the treatment of serious lower respiratory tract infections (including pneumonia) caused by susceptible penicillinase-producing S. aureus ,1,164,167,172 Enterobacter , E. coli , Klebsiella , or S. marcescens .1,164,170,172,181,183

Community-acquired Pneumonia

Although imipenem generally is active against S. pneumoniae (including drug-resistant S. pneumoniae ), imipenem and cilastatin is not included in regimens usually recommended for empiric treatment of community-acquired pneumonia (CAP).512 However, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) state that imipenem is one of several options that can be included in empiric treatment regimens to provide coverage against Ps. aeruginosa in hospitalized patients with CAP who are at risk for Ps. aeruginosa infections (e.g., those with prior Ps. aeruginosa infection, hospitalization and treatment with parenteral anti-infectives in the last 90 days).512

For information regarding the treatment of CAP, current ATS/IDSA clinical practice guidelines available at [Web] should be consulted.512

Nosocomial Pneumonia

Imipenem and cilastatin has been recommended as one option for initial empiric treatment in certain patients with hospital-acquired pneumonia and ventilator-associated pneumonia.6,315

For information regarding the treatment of hospital-acquired and ventilator-associated pneumonia, current ATS/IDSA clinical practice guidelines available at [Web] should be consulted.315

Mycobacterial Infections

ATS, CDC, IDSA, World Health Organization (WHO), and other experts state that imipenem and cilastatin is a possible option for inclusion in multiple-drug regimens used for the treatment of multidrug-resistant (MDR) tuberculosis† (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin).254,255 If a carbapenem (e.g., imipenem and cilastatin) is used in conjunction with other antituberculosis agents for the treatment of MDR tuberculosis, amoxicillin/clavulanate also should be administered with the carbapenem.254,255 Patients with MDR tuberculosis are at high risk for treatment failure and acquisition of further drug resistance, and ATS, CDC, IDSA, and other experts recommend that such patients be referred to or that consultation be obtained from a specialized treatment center as identified by local or state health departments or the CDC.254,255

Imipenem and cilastatin is recommended by ATS, IDSA, and other experts as one of several preferred options for inclusion in multiple-drug regimens used for the treatment of pulmonary infections caused by M. abscessus †.253

Empiric Therapy in Febrile Neutropenic Patients

Imipenem and cilastatin has been used alone or in conjunction with other anti-infectives for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.6,265,266,267,268,269,270,271 Imipenem and cilastatin used alone generally is as effective for empiric therapy in these patients as ceftazidime used alone or ceftazidime used in combination with an aminoglycoside or piperacillin.268,269,271

Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present.275,276,277,279 The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding usual pathogens in these patients and data regarding their in vitro susceptibility to available anti-infective agents.275,277,278,279 The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen.275,277

Reconstitution and Administration

Imipenem and cilastatin sodium is administered by IV infusion.1,5

IV Infusion

Imipenem and cilastatin sodium is commercially available as a powder that must be reconstituted and diluted prior to IV infusion.1,5

Imipenem and cilastatin sodium should not be admixed with other antibacterials.1,5

Reconstitution and Dilution

Single-dose vials containing 250 mg of imipenem and 250 mg of cilastatin or single-dose vials containing 500 mg of imipenem and 500 mg of cilastatin should be reconstituted by adding approximately 10 mL of compatible IV solution (5% dextrose injection; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride injection; 0.9% sodium chloride injection) to provide a suspension.1,5 The suspension should be shaken well and should appear colorless to yellow;1,5 variations in color do not affect potency.1,5

The suspension should then be diluted by transferring into 100 mL of a compatible IV solution.1,5 To ensure complete transfer of vial contents, an additional 10 mL from the IV solution container should be added to the vial and then transferred back into the IV solution container.1,5 The diluted solution should be agitated until it is clear.1,5 Imipenem and cilastatin solutions should be inspected visually for particulate matter prior to administration whenever solution and container permit.1,5

Rate of Administration

The rate of IV infusion of imipenem and cilastatin sodium depends on the dose of imipenem.1,5 If nausea occurs during administration, the infusion rate may be decreased.1,5

The manufacturer recommends that imipenem doses of 500 mg or less should be infused over 20-30 minutes and imipenem doses greater than 500 mg should be infused over 40-60 minutes.1,5

Dosage

Dosage of imipenem and cilastatin is usually expressed in terms of the imipenem content of the fixed combination;1,5 dosage of imipenem monohydrate is expressed in terms of anhydrous imipenem.1,5

Adult Dosage

Dosage of imipenem (administered as imipenem and cilastatin sodium) recommended in adults is based on imipenem susceptibility of the suspected or confirmed causative organism(s) and the patient's renal function.1,5 (For information on definitions of susceptibility to imipenem, see In Vitro Susceptibility Testing under Spectrum.)

For the treatment of infections suspected or proven to be caused by bacteria susceptible to imipenem in adults with creatinine clearance of 90 mL/minute or greater, the manufacturer recommends a dosage of 500 mg of imipenem IV every 6 hours or 1 g IV every 8 hours.1,5

For the treatment of infections suspected or proven to be caused by bacteria with intermittent susceptibility to imipenem in adults with creatinine clearance of 90 mL/minute or greater, the manufacturer recommends a dosage of 1 g of imipenem IV every 8 hours.1,5

The manufacturer states that the maximum IV dosage of imipenem for adults is 4 g daily.1,5

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective therapy in febrile neutropenic patients†, imipenem and cilastatin has been given in a dosage of 500 mg IV every 6 hours.265,266,268

Pediatric Dosage

Dosage of imipenem (administered as imipenem and cilastatin sodium) recommended in pediatric patients is based on the age of the patient.1,5

For the treatment of infections (other than CNS infections) in neonates 4 weeks of age or younger who weigh at least 1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 12 hours in those younger than 1 week of age and 25 mg/kg IV every 8 hours in those 1-4 weeks of age.1,5

For the treatment of infections (other than CNS infections) in infants 4 weeks to 3 months of age who weigh at least 1.5 kg, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1,5

For the treatment of infections (other than CNS infections) in pediatric patients 3 months of age or older, the manufacturer recommends a dosage of 25 mg/kg IV every 6 hours.1,5

The manufacturer states that, based on studies in adults, the maximum IV dosage of imipenem for pediatric patients is 4 g daily.1,5

Dosage in Renal Impairment

Dosage of imipenem (administered as imipenem and cilastatin) must be reduced in adults with creatinine clearance less than 90 mL/minute.1,5 (See Table 1.)

The manufacturer states that imipenem and cilastatin is not recommended in pediatric patients with renal impairment who weigh less than 30 kg since data are not available.1,5

Imipenem and cilastatin sodium should not be used in patients with creatinine clearance less than 15 mL/minute unless hemodialysis is initiated within 48 hours.1,5

Imipenem and cilastatin sodium should be used in hemodialysis patients only if benefits outweigh the potential risk for seizures.1,5 (See Precautions and Contraindications under Cautions.) If the drug is used in patients with creatinine clearances less than 15 mL/minute undergoing hemodialysis, imipenem dosage recommended for patients with creatinine clearances of 15 to less than 30 mL/minute should be used (see Table 1).1,5 Because both imipenem and cilastatin are cleared from the circulation during hemodialysis, the drug should be administered after hemodialysis and at intervals timed from the end of that hemodialysis session.1,5 Dialysis patients, especially those with underlying CNS disease, should be carefully monitored during imipenem and cilastatin treatment.1,5

The manufacturer states that information is insufficient to recommend use of imipenem and cilastatin in patients receiving peritoneal dialysis.1,5

Adverse effects reported with imipenem and cilastatin are similar to those reported with other β-lactam antibiotics,134,146,149,151,156,159,163,174,196,198 and the drug is generally well tolerated.1,134,149,151,156,175,176,186 Adverse CNS effects, including seizures and myoclonus, have been reported occasionally with imipenem and cilastatin.1,134,146,155,162,174,175,179,194,198

GI Effects

Adverse GI effects are among the most frequent adverse reactions to imipenem and cilastatin.134,146,175,183 Nausea,1,127,134,146,149,153,157,162,163,164,169,171,172,175,182,183,196,198 diarrhea,1,134,146,149,157,159,161,162,163,165,167,172,175,182,196 and vomiting1,134,146,149,157,159,161,162,163,164,167,169,171,175,183,196,198 have been reported in up to 4% of patients receiving the drug.1,134,146,196,215 Nausea and vomiting appear to be related to the rate of IV infusion, especially when 1-g doses of the drug are being administered.134,146,159,162,164,215 Nausea and vomiting are generally ameliorated by decreasing the IV infusion rate,146,159,164,196,198,215 but may occasionally be severe enough to require discontinuance of the drug.134,175,183,198,215

Treatment with anti-infectives alters the normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile ).1,302 C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated pseudomembranous colitis) has been reported with nearly all anti-infectives, including imipenem and cilastatin, and may range in severity from mild diarrhea to fatal colitis.1,128,134,146,302 C. difficile produces toxins A and B, which contribute to the development of CDAD;1 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since these infections may be refractory to anti-infective therapy and may require colectomy.1 (See Precautions and Contraindications under Cautions.)

Other adverse GI effects that have been reported in less than 0.2% of patients receiving imipenem and cilastatin include hemorrhagic colitis,1,146,159 gastroenteritis,1 abdominal pain,1 glossitis,1,153 papillar hypertrophy of the tongue,1 staining of the teeth and/or tongue,1 heartburn,1 pharyngeal pain,1,159 taste perversion,1 and increased salivation.159,242

Imipenem and cilastatin therapy generally has only a minimal effect on normal bowel flora.129,133,145,203 Either no decrease or only a slight decrease in total bacterial counts of normal aerobic and anaerobic fecal flora occurs during or following therapy with the drug,129,133,145,203 presumably because only low concentrations of microbiologically active drug are attained in the intestine following IV administration.129,133,145

Hematologic Effects

Eosinophilia1,134,149,159,161,164,167,172,173,175,180,183,196,198 has been reported in up to 4% of patients receiving imipenem and cilastatin.134,196 Transient leukopenia,1,134,174,186 neutropenia,1,134,146,162,164,182,198 agranulocytosis,1,242 pancytopenia,1 bone marrow depression,1 hemolytic anemia,1 thrombocytopenia,1,134,146,162,172,196,198 and thrombocytosis1,134,146,166,173,198 have been reported in less than 2% of patients receiving the drug.1,134,196 Leukocytosis,1 monocytosis,1,146,172 lymphocytosis,1 and basophilia1 have also been reported rarely. Although decreased hemoglobin concentration,1,134,158 decreased hematocrit,1,134,158 and prolonged prothrombin time1,134 have been reported rarely in patients receiving imipenem and cilastatin, a causal relationship to the drug has not been established.1,134

Positive direct antiglobulin (Coombs') test results, without clinical or laboratory evidence of hemolysis, have been reported in about 2%134,196,198 of patients receiving imipenem and cilastatin.1,134,146,157,158,162,165,166,167,171,173,175,183,186,196,198

CNS Effects

Adverse CNS effects have been reported occasionally in patients receiving IV imipenem and cilastatin.1,134,146,155,162,174,175,179,194,198,252 Seizures1,134,146,155,162,174,179,194,198,252 have been reported in up to 1.5%1,134 and dizziness,1 somnolence,1 encephalopathy,1 confusion,1,134,194 myoclonus,1,134,162,194,242,252 tremor,242 paresthesia,1 vertigo,1,260 headache,1,175,194 and psychic disturbances,242 and hallucinations1 have been reported in less than 0.3% of patients receiving the drug IV.1 In most reported cases, seizures or myoclonus occurred in patients with preexisting CNS disorders (e.g., a history of seizures, brain lesions, recent head trauma)134,146,155,162,174,179,194,198,252 and/or who had received relatively high IV dosages of the drug in relation to renal function and body size (e.g., geriatric patients).1,134,146,162,194,198,252 However, seizures have also occurred during imipenem and cilastatin therapy in some patients with no recognized or documented underlying CNS disorder.1,252 Generalized seizures developed during concurrent therapy with ganciclovir and subsided in some patients despite continued ganciclovir therapy when imipenem and cilastatin was discontinued.153,154,155 (See Ganciclovir under Drug Interactions.) Further study is needed to identify other factors that may contribute to the development of adverse CNS effects during IV imipenem and cilastatin therapy, but there is some evidence that the drug may potentiate seizure activity or lower the seizure threshold in patients with other predisposing factors.134,198 Therefore, if imipenem and cilastatin is used in patients with a known seizure disorder, anticonvulsant therapy should be continued during imipenem and cilastatin therapy.1,134,198,252 If focal tremors, myoclonus, or seizures occur in patients receiving imipenem and cilastatin, anticonvulsant therapy should be initiated1,134,198,252 and dosage of imipenem and cilastatin should be decreased or the drug discontinued.1,134,215

Dermatologic and Hypersensitivity Reactions

Hypersensitivity reactions including rash,1,134,146,149,157,159,161,164,174,175,183,191,198 fever,1,134,162,174,198 pruritus,1,134,146,149,162 and urticaria1,134,146,159,162,163,198 have been reported in less than 3% of patients receiving imipenem and cilastatin.1,134,146,198 Allergic dermatitis,1,146 erythema multiforme,1,146,162 facial edema or angioedema,1,146,162 Stevens-Johnson syndrome,1 toxic epidermal necrolysis,1 and flushing1,146,160 have also been reported rarely. Hypersensitivity reactions to imipenem and cilastatin have occurred when the drug was administered to patients hypersensitive to penicillins.134,198,215,245 (See Precautions and Contraindications under Cautions.)

If a hypersensitivity reaction occurs during imipenem and cilastatin therapy, the drug should be discontinued.1 Serious anaphylactic reactions require immediate emergency treatment with appropriate therapy as indicated.1

Renal Effects

Transient increases in BUN and/or serum creatinine concentrations1,134,146 have been reported in less than 2% of patients receiving imipenem and cilastatin.134 Oliguria/anuria, polyuria, proteinuria, discoloration of urine, acute renal failure, and the presence of erythrocytes, leukocytes, bilirubin, urobilinogen, bacteria, or casts in urine have also been reported rarely in patients receiving the drug.1

When given alone, imipenem is nephrotoxic in animals; however, concomitant administration of cilastatin apparently may decrease the nephrotoxic potential of the drug.2,127,131,140,141,148,149 Acute tubular necrosis occurred in rabbits and monkeys who received imipenem alone in doses greater than 100 mg/kg;2,127,131,140,141,148 nephrotoxicity did not occur when 360-mg/kg doses of cilastatin were administered concomitantly with 360-mg/kg doses of imipenem.2,137,141,148,196 Although the mechanism by which cilastatin apparently decreases the nephrotoxic potential of imipenem has not been determined to date, it has been suggested that since cilastatin competes with imipenem for tubular secretion it may protect the kidneys by preventing accumulation of imipenem and/or its metabolites in renal tubular cells.2,141,148 Usual dosages of imipenem and cilastatin do not appear to be nephrotoxic in humans.127 Urinary β₂-microglobulin concentrations were generally unaffected or increased only slightly in healthy adults who received 1-g doses of the drug IV every 6 hours for 10 days.127

Local Effects

Phlebitis and/or thrombophlebitis1,146,149,156,158,159,162,165,167,170,171,173,175,176,183 have generally been reported in 2-5% of patients receiving IV imipenem and cilastatin.1,134,159 In some studies, however, phlebitis occurred in up to 60% of patients receiving the drug.156,171 Phlebitis is generally mild, but may be severe enough to require discontinuance of the drug.156,171,173 Other adverse local reactions, including pain,1,134,159,162 erythema,1,134,146 induration,1,146,165 or infection1 at the IV infusion site, have been reported in 1% or less of patients receiving the drug.1,134

Hepatic Effects

Transient increases in serum concentrations of AST (SGOT),1,127,146,149,155,158,162,163,165,170,172,175,182,198 ALT (SGPT),1,127,146,149,155,158,162,165,170,172,175,182,198 and alkaline phosphatase1,146,149,155,162,163,165,172,174,175,198 have been reported in 2-6% of patients receiving imipenem and cilastatin;134,146 jaundice has been reported in less than 0.2% of patients receiving the drug.1 Increases in serum bilirubin1,146,149,155,162,163 and LDH1 concentrations and hepatitis1 have also been reported rarely.

Other Adverse Effects

Hypotension1,134,146,155 has been reported in less than 1%1,134 and chest discomfort,1 dyspnea,1 hyperventilation,1,149 thoracic spinal pain,1,149 palpitation,1 tachycardia,1 polyarthralgia,1 and asthenia and/or weakness1,149 have been reported in less than 0.2% of patients receiving imipenem and cilastatin.1 Other adverse effects that have been reported in less than 0.2% of patients receiving the drug include cyanosis,1 hyperhidrosis,1 skin texture changes,1 candidiasis,1 pruritus vulvae,1 decreased serum sodium concentrations,1 increased serum potassium and chloride concentrations,1 tinnitus,1 and hearing loss.1,159

Precautions and Contraindications

Imipenem and cilastatin is contraindicated in patients who are hypersensitive to any ingredient in the formulation.1

Prior to initiation of therapy with imipenem and cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics, including penicillins and cephalosporins, or to other allergens.1 There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics,1,134,198,245 and hypersensitivity reactions to imipenem and cilastatin have occurred in patients hypersensitive to penicillins.134,198,215,245 Therefore, imipenem and cilastatin should be used with caution in patients with a history of hypersensitivity reactions to penicillins.210,245

Adverse CNS effects such as confusional states, myoclonus, and seizures have been reported with IV imipenem and cilastatin, particularly when administered in dosages exceeding those recommended by the manufacturer.1,134,146,155,162,174,175,179,194,198,252 (See CNS Effects under Cautions.) Although adverse CNS effects have been reported most frequently in patients with CNS disorders (e.g., a history of seizures, brain lesions, recent head trauma) and/or patients with renal impairment, these effects have also been reported in some patients with no recognized or documented underlying CNS disorders or renal impairment.1,252 Patients with creatinine clearances less than 30 mL/minute, whether or not undergoing hemodialysis, are at increased risk of developing seizures during imipenem and cilastatin treatment.1 Dosage recommendations for imipenem and cilastatin should be adhered to, especially in patients with factors known to predispose to seizures.1,215,252 Anticonvulsant therapy should be continued during imipenem and cilastatin therapy if the drug is used in patients with a known seizure disorder.1,134,198,252 If focal tremors, myoclonus, or seizures occur during imipenem and cilastatin therapy, patients should be evaluated neurologically,242 anticonvulsant therapy should be initiated in patients who are not already receiving such therapy,1,134,198 and the imipenem and cilastatin dosage should be reassessed to determine whether dosage should be decreased or the drug discontinued.1,134,215,252 Safety and efficacy of imipenem and cilastatin have not been established in patients with meningitis and the manufacturer states that the drug should not be used in such patients.1

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with imipenem and cilastatin.1,131,134

Because serum concentrations of imipenem are higher and more prolonged in patients with renal impairment than in patients with normal renal function, doses and/or frequency of administration of imipenem and cilastatin should be decreased in patients with renal impairment.1,134,252 (See Dosage in Renal Impairment under Dosage and Administration.) Patients with severe or marked renal impairment, including those undergoing hemodialysis, have a higher risk of imipenem and cilastatin-induced seizures when receiving the maximum recommended dosage of the drug than do patients with normal renal function.1,252 Therefore, the maximum recommended dosage of the drug should be used in such patients only when clearly needed.1 Patients with creatinine clearances less than 15 mL/minute should not receive imipenem and cilastatin unless hemodialysis is instituted within 48 hours.1 In patients undergoing hemodialysis, imipenem and cilastatin is recommended only when the potential benefit from the drug outweighs the possible risk of drug-induced seizures.1,219 If the drug is used in dialysis patients, particularly those with CNS disorders, careful monitoring is recommended.1

As with other anti-infective agents, prolonged use of imipenem and cilastatin may result in overgrowth of nonsusceptible organisms,1,130,134,146,156,158,159,161,162,166,174,179,191,196,198 especially Candida ,130,158,159,161,162,166,179,191,196,198 enterococci,130 and Pseudomonas .130,156,158,162,166,174,198 Resistant strains of Ps. aeruginosa have developed during therapy with the drug.146,153,157,164,174,183,191,236 Careful observation of the patient during imipenem and cilastatin therapy is essential.1 If superinfection occurs, appropriate therapy should be instituted.1

Because CDAD has been reported with imipenem and cilastatin, it should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drug and managed accordingly.1,302 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1 If CDAD is suspected or confirmed, anti-infectives not directed against C. difficile should be discontinued whenever possible.302 Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.1,302 Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

To reduce development of drug-resistant bacteria and maintain effectiveness of imipenem and cilastatin and other antibacterials, the drug should be used only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1 Information on test methods and quality control standards for in vitro susceptibility testing of antibacterials and specific interpretive criteria for such testing recognized by FDA is available at [Web].1,35 For most antibacterials, including imipenem and cilastatin, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).31,35

Pediatric Precautions

Safety and efficacy of imipenem and cilastatin in pediatric patients is supported by evidence from adequate and well-controlled studies in adults and clinical studies in pediatric patients.1

Adverse effects reported with the drug in neonates and children are similar to those reported in adults and include GI effects (e.g., diarrhea, vomiting, gastroenteritis), rash, urogenital effects (e.g., urine discoloration, oliguria, anuria), and reactions at the site of IV infusion (e.g., phlebitis, IV site irritation).1 Such adverse effects generally have been reported in 1-4% of pediatric patients receiving imipenem and cilastatin.1 However, seizures have been reported in neonates and children 3 months of age or younger receiving the drug.1 In addition, there was a high incidence of seizures in one study in children 3 months to 12 years of age who received imipenem and cilastatin (25 mg/kg IV every 6 hours) for empiric treatment of bacterial meningitis.242 Therefore, because of the risk of seizures, the manufacturer states that IV imipenem and cilastatin should not be used in pediatric patients with CNS infections.1 The manufacturer also states that because there is insufficient data to date evaluating IV imipenem and cilastatin in pediatric patients with impaired renal function who weigh less than 30 kg, the drug should not be used in these patients.1

Diluents containing benzyl alcohol should not be used to prepare imipenem and cilastatin for IV administration to neonates.1 Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.1,272,273 Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates.272,273 Toxicity has not been demonstrated in pediatric patients older than 3 months of age, although small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity.1

Geriatric Precautions

In clinical studies of imipenem and cilastatin involving approximately 2800 adults 18 years of age or older, approximately 800 were 65 years of age or older and 300 were 75 years of age or older.1 There were no apparent differences in safety or effectiveness between these individuals and younger adults and other clinical experience has not revealed evidence of differences in response between these age groups.1 However, the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Imipenem is substantially excreted by the kidney, and the risk of severe adverse reactions may be increased in patients with impaired renal function.1 Limited data indicate that the mean serum half-life of imipenem in healthy geriatric adults 65-75 years of age (with renal function normal for their age) is similar to that expected in individuals with slight renal impairment.1 The manufacturer states that age-based dosage adjustment is not necessary.1 However, because geriatric patients are more likely to have decreased renal function, dosage should be selected with caution in these patients and monitoring of renal function may be useful.1 Dosage should be modified in response to the degree of renal impairment.1 (See Dosage in Renal Impairment under Dosage and Administration.)

Mutagenicity and Carcinogenicity

In vitro studies using imipenem or cilastatin alone in a microbial system (i.e., Ames test), imipenem or imipenem and cilastatin in a mammalian cell system (i.e., V79 mammalian cell mutation assay), or imipenem and cilastatin in an unscheduled DNA synthesis assay have not shown evidence of mutagenicity.1 There also was no evidence of mutagenicity when imipenem and cilastatin was used in an in vivo mouse cytogenicity test.1

Long-term carcinogenicity studies of imipenem and cilastatin have not been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

Both imipenem and cilastatin cross the placenta and are distributed into cord blood and amniotic fluid in humans.209,251

Data available from small numbers of postmarketing cases of imipenem and cilastatin use during pregnancy are insufficient to identify any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

Developmental toxicity studies in animals (mice, rats, rabbits, monkeys) using imipenem and cilastatin (alone or in combination) administered at doses 0.4-2.9 times the recommended human dose (based on body surface area) showed no evidence of drug-induced fetal malformations.1 Embryofetal development studies using imipenem and cilastatin in cynomolgus monkeys at doses similar to the recommended human dose (based on body surface area) showed an increase in embryonic loss.1

Fertility

Reproduction studies in male and female rats using imipenem and cilastatin have not revealed evidence of impaired fertility or effects on reproductive performance.1

Lactation

Imipenem is distributed into milk.219 Data are insufficient regarding the presence of imipenem and cilastatin in human milk and data are not available on possible effects on the breast-fed child or effects on milk production.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for imipenem and cilastatin and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1

Aminoglycosides

The antibacterial activity of imipenem and aminoglycosides is additive or synergistic in vitro against some gram-positive bacteria including Staphylococcus aureus ,8,13 Enterococcus faecalis ,13,19,103,106,109,139 and Listeria monocytogenes .13,19,207 Depending on the method used to determine in vitro synergism, the combination of imipenem and an aminoglycoside is synergistic against 35-98% of E. faecalis tested.103,106,109,139 The combination of imipenem and an aminoglycoside is generally neither synergistic nor antagonistic in vitro against most strains of Pseudomonas aeruginosa and Enterobacteriaceae.8,13,49,57,110,198

-Lactam Antibiotics

In vitro, imipenem antagonizes the antibacterial activity of other β-lactam antibiotics (including aztreonam and most cephalosporins and extended-spectrum penicillins) against many strains of Ps. aeruginosa and some strains of Citrobacter , Enterobacter , Klebsiella pneumoniae , Morganella morganii , and Serratia marcescens .3,13,54,102,107,111,137,198,240,244,247 The antagonism apparently occurs because imipenem, like cefoxitin, is a potent inducer of β-lactamase production and can derepress inducible, chromosomally mediated enzymes in organisms that possess these enzymes.3,13,54,99,102,107,111,137,240 Although inducible β-lactamases have no effect on the antibacterial activity of imipenem, the enzymes inactivate most cephalosporins and penicillins either by hydrolyzing the drugs or by binding to them to prevent access to penicillin-binding proteins.3,13,54,98,102,107,111,137,192,216,240 The clinical importance of this in vitro antagonism has not been determined to date,13,54,102 but imipenem and cilastatin probably should not be used in conjunction with other β-lactam antibiotics.54,102,210,240

Ganciclovir

Generalized seizures have occurred in several patients who received concomitant therapy with IV imipenem and cilastatin and IV ganciclovir.1 Because of the risk of seizures, imipenem and cilastatin should be used concomitantly with ganciclovir only when the potential benefits are thought to outweigh the possible risks.1

Other Anti-infectives

The clinical importance has not been determined to date, but the antibacterial activity of imipenem and co-trimoxazole has generally been synergistic in vitro against Nocardia asteroides .108

Results of an in vitro study using Klebsiella pneumoniae indicate that chloramphenicol can antagonize the bactericidal activity of imipenem.104,111 It has been suggested that if chloramphenicol is used in conjunction with imipenem and cilastatin, chloramphenicol should be administered a few hours after the combination; however, the necessity of this precaution has not been established.104

In an in vitro study using strains of Ps. aeruginosa resistant to aminoglycosides and carbenicillin, the antibacterial activities of imipenem and norfloxacin were synergistic or partially synergistic against about one-third and indifferent against about two-thirds of strains tested; antagonism did not occur.235

Probenecid

Concomitant administration of probenecid and imipenem and cilastatin sodium produces higher and prolonged serum concentrations of cilastatin125,140 but results in only minimal increases in serum concentrations and half-life of imipenem.1,125,140 Therefore, there is no therapeutic benefit from concomitant use of the drugs125,140,215 and the manufacturer of imipenem and cilastatin states that concomitant use of probenecid is not recommended.1

Valproic Acid

In patients receiving valproic acid or divalproex sodium, concomitant use of carbapenems (including imipenem and cilastatin) results in decreased plasma concentrations of valproic acid.1 Because of this interaction, valproic acid concentrations may drop below the therapeutic range and the risk of breakthrough seizures may be increased.1 Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing serum concentrations of valproic acid.1 Increasing the dosage of valproic acid or divalproex sodium in patients receiving a carbapenem may not be sufficient to overcome this interaction.1

Concomitant use of imipenem and cilastatin and valproic acid or divalproex sodium is generally not recommended.1 In patients whose seizures are well controlled on valproic acid or divalproex sodium, use of antibacterials other than carbapenems should be considered to treat infections.1 If concomitant use of imipenem and cilastatin is necessary in such patients, supplemental anti-convulsant therapy should be considered.1 Recommended dosage and dosage schedules should be adhered to, especially in patients with known factors that predispose to convulsive activity.1

Laboratory Test Interferences

Tests for Urinary Glucose

Like most other currently available β-lactam antibiotics, imipenem and cilastatin interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict's solution, Clinitest^®), but does not appear to interfere with glucose oxidase tests (e.g., Diastix^®, Tes-Tape^®).132

Acute Toxicity

If overdosage of imipenem and cilastatin occurs, the drug should be discontinued and the patient treated symptomatically (including supportive measures).1 Imipenem and cilastatin are hemodialyzable.1

Mechanism of Action

Imipenem usually is bactericidal in action.1,2,3,6,13,55,137,148 Like other β-lactam antibiotics, the antibacterial activity of imipenem results from inhibition of mucopeptide synthesis in the bacterial cell wall.1,2,3,55,94,100,148,198 Imipenem has an affinity for and binds to most penicillin-binding proteins (PBPs) of susceptible organisms, including PBPs 1a, 1b, 2, 4, 5, and 6 of Escherichia coli ; PBPs 1a, 1b, 2, 4, and 5 of Pseudomonas aeruginosa ;1,2,94,95,100,111,148,198 and PBPs 1, 2, 3, and 4 of S. aureus .249 In susceptible gram-negative bacteria, imipenem has the greatest affinity for PBP 2 and the lowest affinity for PBP 3.2,4,55,94,95,100,111,148,198 This results in the formation of spheroplasts or ellipsoidal cells without filament formation.2,4,55,94,95,100,111,148,198 Because imipenem also has a high affinity for PBPs 1a and 1b of these organisms, the spheroplasts lyse rapidly.94,100,111,198 Imipenem is able to penetrate the outer membrane of most gram-negative bacteria and gain access to the PBPs3,148,198 more readily than many other currently available β-lactam antibiotics.3,148

In vitro studies indicate that imipenem may have a postantibiotic inhibitory effect against some susceptible organisms.3,55,148,215 Although the mechanism of this postantibiotic effect has not been determined to date, in vitro studies using Staphylococcus aureus , E. coli , and Ps. aeruginosa indicate that following exposure to bactericidal concentrations of imipenem these organisms do not immediately resume growth after the drug is removed.3,55,148,215 It is not known whether a postantibiotic effect occurs in vivo, but it has been suggested that this effect would be beneficial since imipenem may be able to prevent regrowth of susceptible organisms although drug concentrations at the site of infection may fall below the MIC during a dosing interval.55,215

Cilastatin sodium reversibly and competitively inhibits dehydropeptidase I (DHP I).1,2,101,125,140,141,145,148,196,198 Imipenem is hydrolyzed in vivo to a microbiologically inactive metabolite by DHP I present on the brush border of proximal renal tubular cells; concurrent administration of cilastatin prevents this renal metabolism of the antibiotic.1,2,125,137,140,141,148,196,198 The normal physiologic role of DHP I has not been fully elucidated, but the enzyme does not appear to be essential to normal mammalian metabolism.145,148,196 Cilastatin is a specific inhibitor of DHP I and does not inhibit other dipeptidases or bacterial β-lactamases.2,148 Cilastatin has no antibacterial activity1,2,137,140,148,196 and does not affect the mechanism of action of imipenem.2,137,148,196

Spectrum

Imipenem has a spectrum of activity that is broader than that of many other currently available β-lactam antibiotics.1,2,11,13,111,135,145,148,151,196,198 Imipenem is active in vitro against most gram-positive and gram-negative aerobic bacteria1,2,4,13,24,26,41,111,137,148 as well as most gram-positive and gram-negative anaerobic bacteria.1,2,13,63,64,65,67,111,148 The drug also has some activity in vitro against some Mycobacterium ,6,16,81,111 but is inactive against Mycoplasma , Chlamydia , fungi,2,13 and viruses.2,13 Cilastatin has no antibacterial activity and does not affect the antibacterial activity of imipenem when used concomitantly.2,137,140,148,196

In Vitro Susceptibility Testing

For most organisms, inoculum size does not appear to affect susceptibility to imipenem.2,13,41,46,50,86,89,90,111,148,196 MICs of imipenem for Pseudomonas aeruginosa and most Enterobacteriaceae generally are only 2-4 times greater when the size of the inoculum is increased from 10⁵ to 10⁸ colony-forming units (CFU) per mL,13,50,86,89,111,137,148 although MICs for some strains of Enterobacter , Klebsiella , and Proteus may be 4-16 times greater when the inoculum is increased to 10⁸ CFU/mL.13 Results of imipenem susceptibility tests generally are unaffected by the presence of serum.2,137,148

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI), clinical isolates identified as susceptible are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection, resulting in likely clinical efficacy.31 (See Table 2 and Table 3.) Clinical isolates identified as having intermediate susceptibility have MICs or zone diameters that approach usually attainable blood and tissue concentrations and/or for which response rates may be lower than response rates for isolates identified as susceptible.31 The intermediate category also includes a buffer zone for inherent variability in test methods that should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.31 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant , the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs or zone diameters fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.31

CLSI states that strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to imipenem, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.31

Gram-positive Aerobic Bacteria

Gram-positive Aerobic Cocci

Imipenem is generally active in vitro against the following gram-positive aerobic cocci: penicillinase- and nonpenicillinase-producing strains of Staphylococcus aureus 1,2,4,9,13,15,20,21,24,25,26,28,29,30,32,36,37,41,42,111,137,206 and S. epidermidis ,1,2,4,13,15,20,21,26,29,36,41,42,44,111,137 S. saprophyticus ,1 Streptococcus pneumoniae ,1,4,15,22,24,28,41,53,111,137 S. pyogenes (group A β-hemolytic streptococci),1,2,4,15,25,28,41,111,137 group B streptococci (e.g., S. agalactiae ),1,2,4,15,20,23,25,41,111 viridans streptococci,1,15,20 and groups C, G, and H streptococci.1,15,20,111 Unlike cephalosporins and many penicillins, imipenem has some activity against enterococci, although the drug is only bacteriostatic against these organisms.1,2,4,10,13,15,19,20,21,25,26,28,29,32,36,41,103,106,109,111,137,139 Imipenem is active in vitro against many strains of E. faecalis and S. durans ,1,2,4,10,13,15,19,20,21,25,26,28,29,32,36,41,103,106,109,111,137,139 but most strains of S. faecium are considered resistant to the drug.1,2,13,19

The MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of imipenem reported for penicillinase- and nonpenicillinase-producing S. aureus is 0.01-0.5 mcg/mL.2,4,9,13,15,20,21,24,26,28,29,30,32,36,41,137,206 The MIC₉₀ of imipenem for S. epidermidis is generally 0.1-4 mcg/mL,2,4,20,26,29,36,42,44,137 although in a few studies the MIC₉₀ was 32 mcg/mL.13,15,21,111 The in vitro activity of imipenem against staphylococci resistant to penicillinase-resistant penicillins is variable, and a wide range of MIC values has been reported depending on the method used to test susceptibility.2,7,9,13,14,15,18,20,24,26,28,111,137,148,206 In some in vitro studies, when cultures were incubated for up to 18 hours at 30-37°C, the MIC₉₀ of imipenem for methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) ranged from 0.5-8 mcg/mL.2,7,9,13,14,15,18,20,24,26,28,137,206 In other in vitro studies when cultures were incubated for 48 hours at 30 or 35°C, the MIC₉₀ of imipenem for MRSA was 25 mcg/mL or higher and most strains were considered resistant to the drug.1,15,18,111,148,206 Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to imipenem.31

The MIC₉₀ of imipenem reported for S. pneumoniae is 0.01-1 mcg/mL,4,13,20,22,24,28,41,53,137 and the MIC₉₀ of the drug for S. pyogenes ,2,4,13,15,20,25,28,41,137 viridans streptococci, or groups B, C, G, or H streptococci2,4,13,15,20,23,25 is 0.01-0.125 mcg/mL.

The MIC₉₀ of imipenem reported for E. faecalis is 0.3-4 mcg/mL.10,13,15,19,20,21,25,26,28,41,103,106,109,139 Imipenem is less active in vitro against E. faecium than E. faecalis .1,2,13,19,39 The MIC₉₀ of imipenem reported for S. faecium ranges from 0.5-50 mcg/mL,2,10,19,139 and most strains are considered resistant to the drug.1,2,13,19 Imipenem is not bactericidal against enterococci.2,10,13,19,103,106,109 Although results vary depending on the method used to test bactericidal activity, the MBC₉₀ (minimum bactericidal concentration of the drug at which 90% of strains tested are killed) of imipenem for most strains of E. faecalis is 64 mcg/mL or greater.10,13,19,103,106

Gram-positive Aerobic Bacilli

Imipenem is active in vitro against most strains of Listeria monocytogenes ,1,15,17,19,28,111,137,207,221 but the drug is not generally bactericidal against this organism.19,111,207 The MIC₉₀ of imipenem reported for L. monocytogenes is 0.015-4 mcg/mL,15,17,19,28,111,137,207,221 and the MBC₉₀ ranges from 0.25-250 mcg/mL.19,111,207

Imipenem is active in vitro against Bacillus , including B. cereus .1

Imipenem also is active in vitro against some strains of Nocardia asteroides ,1,13,71,73,80,108,137 and the MIC₉₀ of the drug reported for this organism is 0.19-8 mcg/mL.13,71,73,80,108,137

The mean MIC₉₀ of imipenem for Erysipelothrix rhusiopathiae reportedly is 0.015 mcg/mL.111 Corynebacterium generally are resistant to imipenem and have a mean MIC₉₀ of the drug of more than 32 mcg/mL.111

Gram-negative Aerobic Bacteria

Neisseria

Imipenem is active in vitro against Neisseria meningitidis 4,28,39,45,111,137 and most strains of penicillinase- and nonpenicillinase-producing Neisseria gonorrhoeae .1,4,24,25,28,39,111,137 The MIC₉₀ of imipenem is 0.03-0.11 mcg/mL for N. meningitidis 4,13,28,39,45,137 and 0.12-0.64 mcg/mL for nonpenicillinase- or penicillinase-producing N. gonorrhoeae .4,24,25,28,39,137

Haemophilus

Imipenem is active in vitro against most β-lactamase- and non-β-lactamase-producing strains of Haemophilus influenzae 1,4,13,21,24,25,28,46,111,137,212,218,243 and H. parainfluenzae .1,212 The MIC₉₀ of the drug reported for H. influenzae 4,21,24,25,28,46,137,218,243 and H. parainfluenzae 212 is 0.25-8 mcg/mL. Imipenem is active in vitro against strains of H. influenzae resistant to ampicillin and/or chloramphenicol218,243 as well as some strains resistant to ampicillin, chloramphenicol, and co-trimoxazole.243 H. ducreyi also are inhibited in vitro by imipenem.1

Enterobacteriaceae

Imipenem is active in vitro against most clinically important Enterobacteriaceae, including Citrobacter diversus ,1,4,28,42,111 C. freundii ,1,4,25,28,41,42,111 Enterobacter agglomerans ,28,111 E. cloacae ,1,4,24,28,30,36,41,42,111,137 E. aerogenes ,1,4,24,28,30,41,42,111,137 Escherichia coli ,1,2,4,21,24,25,26,28,29,30,32,34,41,42,59,111 Hafnia alvei ,1,111 Klebsiella oxytoca ,1,32,42,111 K. pneumoniae ,1,4,26,28,30,32,36,42,51,111,137 Morganella morganii ,1,4,24,26,28,29,32,34,41,42,111,137 Proteus mirabilis ,1,4,24,25,26,29,32,34,41,42,111,137 P. vulgaris ,1,24,26,28,29,34,41,42,111,137 Providencia rettgeri ,1,4,24,26,28,34,111,137 P. stuartii ,1,4,24,25,28,36,41,51,111 Serratia liquefaciens ,1 S. marcescens ,1,4,24,25,26,28,32,41,42,43,44,51,111,137 Salmonella ,1,4,26,28,41,47,111,137 Shigella ,1,4,26,28,111,137 Yersinia enterocolitica ,1,25,26,75,111,137,221 and Y. pseudotuberculosis .1

The MIC₉₀ of imipenem reported for C. diversus ,4,28,42 C. freundii ,4,25,28,41,42 E. aerogenes ,4,24,28,30,36,41,42,137 E. agglomerans ,28 E. cloacae ,4,24,28,30,36,41,42,137 E. coli ,2,4,21,24,26,28,29,30,32,34,41,42 K. oxytoca ,32,42 K. pneumoniae ,4,26,28,30,36,42,51,137 and Y. enterocolitica 25,26,75,137,221 is 0.1-4 mcg/mL. The MIC₉₀ for M. morganii ,4,24,26,28,29,32,34,41,42,137 P. mirabilis ,4,24,25,26,29,32,34,41,42,137 P. vulgaris ,24,26,28,29,34,41,42,137 P. rettgeri ,4,24,26,28,34,137 P. stuartii ,4,24,25,28,36,41,51 and S. marcescens 4,24,25,26,28,32,41,42,43,44,51,137 is 0.5-8 mcg/mL.

The MIC₉₀ of imipenem reported for Salmonella is 0.1-2 mcg/mL.4,26,28,41,137 In one study, the MIC₉₀ of the drug for S. enteritidis and S. typhi was 0.25-0.5 mcg/mL.47 The MIC₉₀ of imipenem reported for Shigella is 0.1-0.5 mcg/mL.4,26,28,137

Pseudomonas

Imipenem is active in vitro against many strains of Pseudomonas aeruginosa .1,4,13,24,25,26,28,29,32,37,41,42,44,48,49,51,52,57,58,59,111,137 In vitro on a weight basis, the activity of imipenem against Ps. aeruginosa appears to be approximately equal to or slightly greater than that of ceftazidime.48,49,57,59,111,240 In addition, imipenem is active in vitro against some strains of Ps. aeruginosa resistant to third generation cephalosporins, aminoglycosides, and extended-spectrum penicillins.13,51,56,58,60,240 The MIC₉₀ of imipenem reported for Ps. aeruginosa is 1.1-16 mcg/mL.4,24,25,26,28,29,32,36,37,41,42,44,48,49,51,52,57,58,59,137

Imipenem is also active against some Pseudomonas other than Ps. aeruginosa .1,13,37,78,111 The MIC₉₀ of imipenem reported for Ps. acidovorans ,37 Ps. fluorescens ,37 Ps. putida ,37,78 and Ps. stutzeri 37,78 is 0.5-2.5 mcg/mL.

Other Gram-Negative Aerobic Bacteria

Imipenem is active in vitro against Acinetobacter .1,25,26,28,34,37,38,52,78,111,137 The MIC₉₀ of the drug reported for A. calcoaceticus var. anitratus is 0.25-0.5 mcg/mL,25,34,37,38,78 and the MIC₉₀ reported for A. calcoaceticus var. lwoffi is 0.15-0.39 mcg/mL.34,37,38,78

Moraxella catarrhalis generally is inhibited in vitro by imipenem concentrations of 0.03-0.12 mcg/mL.250

Imipenem is active in vitro against Bordetella bronchiseptica ,1,78,111 Eikenella corrodens ,72,84,111 and Pasteurella multocida .1,111 The MIC₉₀ of the drug reported for B. bronchiseptica 78,111 and E. corrodens 72,84,111 is 0.25-4 mcg/mL.

Brucella melitensis 70,111,137 is inhibited in vitro by imipenem concentrations of 0.33-2 mcg/mL. Imipenem also is active in vitro against Alcaligenes denitrificans ,1,78,137 A. xylosoxidans ,37,78,111 Aeromonas hydrophila ,1,111 and Plesiomonas shigelloides .1 The MIC₉₀ of imipenem reported for A. xylosoxidans and A. denitrificans is 1.3-8 mcg/mL.37,78,137

Imipenem has some activity in vitro against Flavobacterium ,37,78 but the MIC₉₀ of imipenem reported for Chryseobacterium meningosepticum is usually 20-32 mcg/mL and most strains of the organism are considered resistant to the drug.37,78,111

Imipenem is active in vitro against some strains of Brevundimonas diminuta .78 While some strains of Burkholderia cepacia are inhibited in vitro by imipenem concentrations of 16 mcg/mL or less,37,78 most strains of the organism are resistant to the drug.1,13,111

Imipenem is active in vitro against Capnocytophaga .301,303,306 The MIC₉₀ of imipenem reported for Capnocytophaga is 0.5 mcg/mL.303

Imipenem is active in vitro against Campylobacter coli , C. fetus subsp. fetus , and C. jejuni , including β-lactamase-producing strains.25,77,287,288,289 The MIC₉₀ of imipenem reported for C. fetus subsp. fetus is 0.03-0.125 mcg/mL.25,77,287

The MIC₉₀ of imipenem for Helicobacter pylori ( C. pylori ) reportedly is 0.13 mcg/mL.246

In vitro, Legionella pneumophila generally are inhibited by imipenem concentrations of 0.03-0.25 mcg/mL.12,212

Gardnerella vaginalis reportedly are inhibited in vitro by imipenem.1

Stenotrophomonas maltophilia generally is resistant to imipenem.1,13,26,37,42,78,111

Anaerobic Bacteria

Imipenem is active in vitro against most gram-positive anaerobic bacteria including Actinomyces ,1,16,62,202 Bifidobacterium ,16 Clostridium ,1,2,16,25,42,61,62,64,65,74,136,137,202 Eubacterium ,1,2,16,61,62,202 Lactobacillus ,16,62 Peptococcus ,1,2,16,61,62,63,64,65,202 Peptostreptococcus ,1,2,16,62,63,64,65,202 and Propionibacterium .1,16,62,79,137,202 The MIC₉₀ of imipenem reported for most of these gram-positive anaerobic bacteria is 0.015-4 mcg/mL.2,16,61,62,63,64,74,79,137,202 C. perfringens are generally inhibited in vitro by imipenem concentrations of 0.015-1.3 mcg/mL.2,16,64,65,74,137,202 Unlike most other currently available β-lactam antibiotics, imipenem is active in vitro against some strains of C. difficile .2,13,42,61,64,136,137 The MIC₉₀ of the drug reported for C. difficile is 2-16 mcg/mL.2,13,42,61,64,136,137,202

Imipenem is active in vitro against gram-negative anaerobic bacteria including most strains of Bacteroides ,1,2,21,28,42,61,62,63,64,65,66,67,68,69,135,138,202 Fusobacterium ,1,2,28,62,63,64,65,136,202 Leptotrichia buccalis ,61,62 Prevotella , and Veillonella .1,2,16,61,62,63,64

The MIC₉₀ of imipenem reported for Bacteroides fragilis ,21,28,61,62,64,65,66,67,68,69,135,138,202 B. distasonis ,61,64,65,67,69,135 B. ovatus ,64,67,69,135 B. thetaiotaomicron ,42,61,64,65,67,69,135,202 and B. vulgatus 64,65,67,69,135 is 0.03-4 mcg/mL. Imipenem is active in vitro against some strains of Bacteroides , including B. fragilis , resistant to clindamycin and cefoxitin.2,13,64,138

Prevotella bivia , P. disiens , P. melaninogenica , and P. oralis are inhibited in vitro by imipenem concentrations of 4 mcg/mL or less.1,61,63,65,69,202

The MIC₉₀ of imipenem reported for Fusobacterium ,2,16,28,62,63,64,65,136,202 L. buccalis ,62 and Veillonella 2,16,61,62,63,64 is 0.015-2 mcg/mL.

Other Organisms

The clinical importance has not been determined to date, but imipenem is active in vitro against some Mycobacterium including M. abscessus ,6 M. chelonae ,6 M. fallax ,16,27 and M. fortuitum .6,16,81,111 In one study, 1012 isolates of M. fortuitum were inhibited in vitro by imipenem concentrations of 6.25 mcg/mL.81

Although a few strains of Chlamydia trachomatis were inhibited in vitro by imipenem in one study,83 the mean MIC₉₀ of the drug for C. trachomatis usually is 32 mcg/mL or higher and the organism is considered resistant to imipenem.82,111

Resistance

Imipenem has a high degree of stability against hydrolysis by bacterial β-lactamases, including both plasmid-mediated and chromosomally mediated enzymes.2,3,111,137,148,151 The drug generally is more stable against inactivation by β-lactamases than are cefoxitin, cefotaxime, or cefuroxime.3 Imipenem generally is stable against hydrolysis by staphylococcal β-lactamases and β-lactamases classified as Richmond-Sykes types I, II, III (TEM type), IV, or V (PSE and OXA types),2,3,111,137,148,151 but is inactivated by a β-lactamase produced by Bacteroides fragilis .3,111 Although imipenem is hydrolyzed to some extent by a β-lactamase produced by Stenotrophomonas maltophilia ,2,145,151,198 resistance to imipenem in this organism may also be related to other factors since this enzyme has a low affinity for the drug.2,137

Resistance to imipenem in gram-positive bacteria, including Staphylococcus epidermidis and methicillin-resistant staphylococci, is generally the result of altered penicillin-binding proteins (PBPs).3,148 In vitro exposure of some strains of methicillin-resistant S. aureus (MRSA) to imipenem has induced imipenem resistance in strains that were originally susceptible to the drug.13,92 Tolerance to the bactericidal effects of imipenem has been reported in enterococci2,3,13,111,137 and some strains of Listeria monocytogenes 3,13,111 and methicillin-resistant staphylococci.3,13,137,148 Although most susceptible organisms have an MBC of imipenem that is 1-4 times greater than the MIC of the drug,3,13,57,111,137,148 bacteria that are tolerant to imipenem have an MBC that is at least 16 times higher than the MIC.3,13,57,111

Resistant strains of Ps. aeruginosa have developed during therapy with imipenem1,137,146,153,157,162,163,164,173,174,183,191,196,198,222,236,238,240 and have resulted in treatment failures in some cases.153,157,162,164,183,198,222 The mechanism of imipenem resistance in these organisms is unclear,3,153,222,240 but resistance may develop rapidly following initiation of therapy with the drug.1,153,162,222 Resistance to imipenem in Ps. aeruginosa appears to result from chromosomal β-lactamase activity and decreased permeability due to loss of an outer-membrane porin protein (OprD2) or may result from a plasmid-mediated metallo-β-lactamase.222,238,240,262,263,264 Tolerance to the bactericidal effects of imipenem has been reported in some strains of Ps. aeruginosa .3,13,57

In vitro studies indicate that imipenem, like cefoxitin, is a potent inducer of β-lactamases and can reversibly derepress inducible, chromosomally mediated β-lactamases in Ps. aeruginosa and Enterobacteriaceae that possess these enzymes.3,13,54,98,102,107,111,137,192,216,237,238,239,240,248 Although these enzymes inactivate aztreonam and most cephalosporins and penicillins either by hydrolyzing the drugs or by binding to them to prevent access to PBPs, these β-lactamases have no effect on the antibacterial activity of imipenem.3,13,54,98,102,107,111,137,192,216,237,239,240 (See β-Lactam Antibiotics under Drug Interactions.) Imipenem does not appear to select mutants derepressed for β-lactamase production.237,248

Cross-resistance generally does not occur between imipenem and other anti-infective agents, including cephalosporins, penicillins, and aminoglycosides.2,3,137,148,236,238 However, strains of Ps. aeruginosa resistant to imipenem that also were resistant to meropenem have been reported.264

Pharmacokinetics

Cilastatin prevents metabolism of imipenem by dehydropeptidase I (DHP I) present on the brush border of proximal renal tubular cells and, when administered concomitantly, results in urinary concentrations of active imipenem that are higher than could be obtained following administration of the antibiotic alone.1,2,118,120,125,137,140,141,148,196,198 Concomitant cilastatin also results in a slight increase in serum concentrations of imipenem, but does not appreciably affect its serum half-life.118,120,140,198 Imipenem has no effect on the pharmacokinetics of cilastatin sodium.115,120,140

Unless specified otherwise, serum and tissue concentrations of imipenem and pharmacokinetic parameters presented for imipenem and cilastatin were obtained from studies where imipenem monohydrate and cilastatin sodium were administered concomitantly in a 1:1 ratio. Imipenem is administered as the monohydrate, but dosages and concentrations of the drug are expressed in terms of anhydrous imipenem.1 Dosage of imipenem and cilastatin is expressed in terms of the imipenem content of the drug.1

Absorption

Neither imipenem nor cilastatin is appreciably absorbed from the GI tract and, therefore, imipenem and cilastatin must be given parenterally.125,143

Following IV infusion over 20-30 minutes of a single 250-mg, 500-mg, or 1-g dose of imipenem and cilastatin in healthy adults with normal renal function, peak serum concentrations of imipenem immediately following completion of the infusion range from 14-24, 21-58, and 41-83 mcg/mL, respectively.1,114,125 Serum concentrations declined to 1.5 mcg/mL or less at 4-6 hours after these doses.1,114,125 In adults with infections who receive 500-mg or 1-g doses of imipenem and cilastatin by IV infusion over 30-60 minutes every 6 hours, peak serum imipenem concentrations are 19.3-38.3 or 16.7-67.3 mcg/mL, respectively, and trough concentrations average 1 or 3.1 mcg/mL, respectively.208

Following IV infusion over 15-20 minutes of a single 25-mg/kg dose of imipenem and cilastatin in children 2-12 years of age with infections, serum imipenem concentrations 0.5 and 6 hours after the dose average 33.5 and 0.79 mcg/mL, respectively.144 In children 3 months to 13 years of age with infections who received imipenem and cilastatin in a dosage of 60-100 mg/kg daily, peak serum imipenem concentrations at steady state ranged from 12.8-80.8 mcg/mL and trough serum concentrations ranged from 0-0.7 mcg/mL.160 In neonates 1-8 days of age with infections who received a single 25-mg/kg dose of the drug, serum imipenem concentrations averaged 97.3, 45.5, 30.6, 14.4, 3.1, and 0.9 mcg/mL immediately following completion of the infusion and 1, 2, 4, 8, and 12 hours later, respectively.117 In a dose-ranging study in premature, low-birthweight neonates (0.7-1.9 kg) 1 week of age or younger who received imipenem and cilastatin in a dosage of 20 mg/kg every 12 hours given IV over 15-30 minutes, mean peak and trough plasma concentrations averaged 43 and 1.7 mcg/mL, respectively.1 While the clinical importance is unclear, multiple IV doses of imipenem and cilastatin in neonates may result in moderate accumulation of cilastatin.1

No accumulation of imipenem or cilastatin occurs following multiple doses in patients with normal renal function.1

Distribution

Following IV administration, imipenem is distributed into saliva,208 sputum,1,208,215 aqueous humor,1,215 bone,1,182,208,215 bile,1,215 reproductive organs,1 myometrium,215 endometrium,215 heart valve,215 intestine,215 and pleural,1 peritoneal,1,215 interstitial,1 blister,142 and wound208,215 fluids.

In adults, the apparent volume of distribution of imipenem in the central compartment (V_c) averages 0.16 L/kg and the volume of distribution at steady state (V_ss) averages 0.23-0.35 L/kg.114,116,122,124,208 In children 2-12 years of age, V_c averages 0.326 L/kg.144 In neonates 1-8 days of age, V_ss ranges from 0.251-0.418 L/kg.117

Only low concentrations of imipenem diffuse into CSF following IV administration; CSF concentrations are generally 1-10% of concurrent serum concentrations.1,117,188,205 Following a single 1-g IV dose of imipenem and cilastatin in patients with uninflamed meninges, CSF concentrations approximately 1 hour after the dose average 0.8 mcg/mL.1 In children 4 months to 11 years of age with meningitis who received 25-mg/kg IV doses of the drug every 6 hours, CSF imipenem concentrations ranged from 0.27-3.5 mcg/mL in samples obtained 1.5-3.6 hours after a dose; serum concentrations 1.7-3.1 hours after the dose ranged from 2.9-25 mcg/mL.205 CSF imipenem concentrations in these children did not appear to be affected by the degree of meningeal inflammation.205

Imipenem is 13-21%1,125 and cilastatin is approximately 40%1 bound to serum proteins.

Both imipenem and cilastatin cross the placenta and are distributed into cord blood and amniotic fluid.209,251 In one study in pregnant women who received a single 500-mg IV dose of imipenem and cilastatin, amniotic fluid concentrations varied greatly.209 In women in early pregnancy, mean amniotic fluid concentrations in samples taken 3 hours after the dose were 47% of simultaneous maternal plasma concentrations; in women in late pregnancy, mean concentrations were 16% of simultaneous maternal plasma concentrations in samples obtained 30 minutes after the dose.209 Imipenem is distributed into milk.219

Elimination

Serum imipenem concentrations appear to decline in a biphasic manner following IV administration of imipenem and cilastatin in adults with normal renal function.114,122,124 In adults with normal renal function, the distribution half-life of IV imipenem averages 0.23-0.31 hours114,122,124 and the elimination half-life averages 0.85-1.3 hours.1,114,122,124,125,140,143 In healthy geriatric adults 65-75 years of age (with renal function normal for their age) who received a single dose of 500 mg of imipenem and 500 mg of cilastatin given IV over 20 minutes, the mean plasma half-lives of imipenem and cilastatin were 1.5 and 1.1 hours, respectively, and were similar to half-lives expected in individuals with slight renal impairment.1 Multiple doses have no effect on the pharmacokinetics of imipenem or cilastatin and accumulation does not occur.1

The elimination half-life of IV imipenem averages 1-1.3 hours in children 2-12 years of age144 and 1.5-2.6 hours in neonates 1-10 days of age.117,118 IV cilastatin has an elimination half-life of 0.83-1.1 hours in adults with normal renal function1,114,116,125,140 and 3.1-8.8 hours in neonates.117,118

If imipenem is administered alone, the drug is partially hydrolyzed in the kidneys by DHP I to a microbiologically inactive metabolite and only 5-43% of the dose is excreted unchanged in urine.1,125,140,143,148 However, when cilastatin is administered concurrently with imipenem in a 1:1 ratio as a suspension or solution, approximately 50 or 70% of the imipenem dose, respectively, and approximately 75% of the cilastatin dose are excreted unchanged in urine within 10 hours.1,2,118,120,125,137,140,141,143,148,196,198 In adults, maximal urinary concentrations of active imipenem are obtained with a 4:1 ratio of imipenem to cilastatin; however, a 1:1 ratio of imipenem to cilastatin ensures that DHP I is inhibited for up to 8-10 hours.2,123,140 Urinary imipenem concentrations may be greater than 10 mcg/mL for up to 8 hours following a single 500-mg IV dose of imipenem and cilastatin.1

Imipenem is also metabolized to some extent by a nonrenal mechanism unrelated to DHP I.2,115,140,204 Approximately 20-30% of an imipenem dose is inactivated by nonspecific hydrolysis of the β-lactam ring.2,115,140,204 Although the microbiologically inactive metabolite is identical to that formed by renal DHP I, this nonspecific hydrolysis is unaffected by concurrent administration of cilastatin.2,140,204

Cilastatin is partially metabolized in the kidneys to N -acetylcilastatin,2,125,140,148 which is also an effective inhibitor of DHP I.2 Approximately 70-80% of an IV dose of cilastatin is excreted in urine unchanged114,115,125,140,148 and 12% is excreted as N -acetylcilastatin.115,125,140 The metabolic fate of the remainder of the dose has not been elucidated to date.125

Imipenem, cilastatin, and their metabolites are excreted principally in urine by both glomerular filtration and tubular secretion.2,115,123,125,140,148 Approximately 20-30% of the renal clearance of imipenem occurs by tubular secretion;2,123,140 however, cilastatin competitively inhibits active tubular secretion of imipenem.2,148 Less than 1% of an imipenem dose and less than 2% of a cilastatin dose are excreted in feces following IV administration.3,115,140

In adults with normal renal function, plasma clearance of imipenem and of cilastatin ranges from 165-207 and 207-218 mL/minute per 1.73 m², respectively.3,114 Plasma clearance of imipenem averages 270 mL/minute per 1.73 m² in children 2-12 years of age144 and 3.4 mL/minute per kg in neonates 1-10 days of age.118

The serum half-lives of both imipenem and cilastatin are prolonged in patients with impaired renal function; however, the half-life of cilastatin is prolonged to a greater extent than that of imipenem.120,126,185 The serum half-life of IV imipenem and of cilastatin averages 2.1 and 2.5 hours, respectively, in adults with creatinine clearances of 17-33 mL/minute per 1.73 m², and 2.7-3.7 and 7-17 hours, respectively, in adults with creatinine clearances less than 10 mL/minute per 1.73 m².120,125

Both imipenem and cilastatin are removed by hemodialysis;120,126,140,185 however, the amount of the drugs removed during hemodialysis varies considerably depending on several factors (e.g., type of coil used, dialysis flow rate).120,126,185 In patients who received a single 250- or 500-mg dose of imipenem and cilastatin, a 3- to 4-hour period of hemodialysis removed 20-90% of the imipenem dose and 38-82% of the cilastatin dose into the dialysate.120,126,185 Imipenem and cilastatin are removed by peritoneal dialysis.241

Chemistry and Stability

Chemistry

Imipenem and cilastatin sodium is a fixed combination of imipenem monohydrate and the sodium salt of cilastatin.1

Imipenem is a semisynthetic carbapenem antibiotic2,4,148,196,198 and is the crystalline N -formimidoyl derivative of thienamycin, a carbapenem antibiotic produced by Streptomyces cattleya .1,2,148,196,198 Carbapenems are β-lactam antibiotics that contain a fused β-lactam ring and 5-membered ring system similar to that contained in penicillins; however, the 5-membered ring in carbapenems is unsaturated and contains a carbon rather than a sulfur atom.2,4,148,196,198 Imipenem has a hydroxyethyl group at position 6 of the β-lactam ring rather than the acylamino group present at this position in penicillins and cephalosporins; the hydroxyethyl group in imipenem has a trans configuration unlike the acylamino groups in penicillins and cephalosporins which have a cis configuration.2,148,196,198 These structural differences result in increased antibacterial activity and stability against hydrolysis by most β-lactamases.2,148,196,198 Imipenem contains a basic alkylthio side chain on the 5-membered ring; this side chain results in antipseudomonal activity.148,215

Cilastatin sodium, the sodium salt of a derivatized heptenoic acid,1,2 is a specific and reversible inhibitor of dehydropeptidase I (DHP I).1,2,101,125,140,141,145,148,196,198 DHP I is a dipeptidase present on the brush border of proximal renal tubular cells which inactivates imipenem by hydrolyzing the β-lactam ring.2,101,125,140,141,145,148,196,198 Concomitant use of cilastatin prevents in vivo metabolism of imipenem by DHP I and results in urinary concentrations of active imipenem that are higher than could be obtained following use of the antibiotic alone.1,2,125,137,140,141,148,196,198 (See Pharmacokinetics.)

Imipenem and cilastatin sodium is commercially available as a sterile powder for injection for IV use that contains a 1:1 ratio of imipenem to cilastatin.1 Commercially available imipenem and cilastatin sodium for injection contains 3.2 mEq of sodium per gram of imipenem.1 Potency of imipenem monohydrate is expressed in terms of imipenem, calculated on the anhydrous basis, and potency of cilastatin sodium is expressed in terms of cilastatin.1

Imipenem monohydrate occurs as a white or off-white, nonhygroscopic, crystalline compound1 and has solubilities of 11 mg/mL in water at room temperature2 and approximately 0.2 mg/mL in alcohol at 25°C.219 Cilastatin sodium occurs as an off-white to yellowish-white, hygroscopic, amorphous compound1 and has solubilities of greater than 2 g/mL in water and approximately 6 mg/mL in alcohol at 25°C.219

When imipenem and cilastatin sodium powder for injection for IV use is reconstituted and diluted as directed by the manufacturer, solutions of the drug are clear and colorless to yellow1 and have a pH of 6.5-8.5.1

Stability

Commercially available imipenem and cilastatin sodium sterile powder for injection for IV infusion should be stored at less than 25°C.1,5

The manufacturer states that following reconstitution of imipenem and cilastatin sodium powder with 10 mL of an appropriate IV solution (5% dextrose injection; 5% dextrose and 0.225, 0.45, or 0.9% sodium chloride injection; 0.9% sodium chloride injection), the resulting suspension of the drug maintains satisfactory potency for 4 hours at room temperature or 24 hours when refrigerated at 5°C.1,5 Reconstituted suspensions and final diluted solutions of the drug should not be frozen.1,5

The stability of imipenem is temperature and pH dependent.93,112,119,204 Solutions of imipenem and cilastatin sodium should not be frozen1 since freezing at temperatures warmer than -70°C results in decomposition of the drug similar to that observed with ampicillin.219 The drug is inactivated at alkaline or acidic pH, but is generally stable at neutral pH.113 Imipenem is unstable in vitro at room temperature, 35-37°C, or -20°C in serum or urine113,119,143,204 and in certain media used for in vitro susceptibility testing.93

Suspensions and solutions of imipenem and cilastatin sodium may darken (i.e., IV solutions may turn deep yellow) with time;219 color variations do not indicate loss of potency.1 However, IV solutions of the drug should be discarded if they become brown.219

1. Merck Sharp & Dohme. Primaxin^® IV (imipenem and cilastatin sodium for injection, powder for solution) prescribing information. White House Station, NJ. 2019 Sep.

2. Birnbaum J, Kahan FM, Kropp H et al. Carbapenems, a new class of beta-lactam antibiotics. Am J Med . 1985; 78(Suppl 6A):3-21. [PubMed 3859213]

3. Neu HC. Carbapenems: special properties contributing to their activity. Am J Med . 1985; 78(Suppl 6A):33-40. [PubMed 3873871]

4. Neu HC. Structure-activity relations of new β-lactam compounds and in vitro activity against common bacteria. Rev Infect Dis . 1983; 5(Suppl 2):S319-36. [PubMed 6342103]

5. Fresenius Kabi, USA. Primaxin^® Imipenem and cilastatin sodium for injection, powder for solution prescribing information. Lake Zurich, IL. Aug 2020.

6. Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:.

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